Phase 1B study of amuvatinib in combination with five standard cancer therapies in adults with advanced solid tumors
| Autor: | Aram Oganesian, Monica M. Mita, Amarpal Sahai, Sanjeev Redkar, Michael S. Gordon, Lee S. Rosen, Pietro Taverna, Nirmal Kapoor, Anthony W. Tolcher, Mohammad Azab, Robert G. Bristow, Gavin Choy |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Cancer Research Lung Neoplasms Receptor Platelet-Derived Growth Factor alpha DNA Repair medicine.drug_class medicine.medical_treatment Pharmacology Toxicology Amuvatinib Piperazines Cohort Studies Growth factor receptor Carcinoma Non-Small-Cell Lung Antineoplastic Combined Chemotherapy Protocols medicine Humans Drug Interactions Pharmacology (medical) Doxorubicin Protein Kinase Inhibitors Etoposide Neoplasm Staging Chemotherapy Dose-Response Relationship Drug business.industry Thiourea Cancer Drug Synergism Middle Aged medicine.disease Small Cell Lung Carcinoma Tumor Burden Neuroendocrine Tumors Proto-Oncogene Proteins c-kit Pyrimidines Oncology Cancer research Female Topotecan business Topoisomerase inhibitor DNA Damage Half-Life medicine.drug |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 74:195-204 |
| ISSN: | 1432-0843 0344-5704 |
| Popis: | Amuvatinib is an oral multi-kinase inhibitor that suppresses RAD51, inhibits mutant c-KIT and platelet-derived growth factor receptor alpha, and has synergistic activity with DNA-damaging agents and topoisomerase inhibitors such as etoposide, doxorubicin, and topotecan. We conducted a phase 1B study to estimate the maximum tolerated dose (MTD) levels of amuvatinib with standard chemotherapy regimens and to define the safety profiles of specific amuvatinib + standard regimens.Five therapies each co-administered with amuvatinib 100-800 mg/day every 21 days were evaluated in treatment-naïve or moderately pre-treated subjects: paclitaxel IV followed by carboplatin IV; carboplatin IV followed by etoposide; topotecan IV; docetaxel IV; and erlotinib by mouth.Among 97 treated subjects, no treatment arm reached the MTD. Dose-limiting toxicities included febrile neutropenia and diarrhea. No pharmacokinetic interactions of amuvatinib with any cancer regimens occurred. Of 12/97 (12 %) partial responses overall, 11 were seen in the amuvatinib and paclitaxel/carboplatin or carboplatin/etoposide arms and most commonly in the neuroendocrine (NE), non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC) tumors. Forty-four subjects (45 %) had stable disease. Adverse events reflected combination treatment and were primarily non-hematologic (fatigue, alopecia, diarrhea, nausea, anorexia) and hematologic (neutropenia, anemia, thrombocytopenia, leukopenia). Pharmacodynamic effects as measured by decreased levels of RAD51 and increased residual DNA damage (53BP1 foci) were seen in skin punch biopsies.Amuvatinib was well tolerated, modulated RAD51, and showed antitumor activity when combined with paclitaxel/carboplatin and carboplatin/etoposide in NE, NSCLC, and SCLC tumors. |
| Databáze: | OpenAIRE |
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